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Role of Topoisomerase IIß in the Resistance of 9-OH-ellipticine-resistant Chinese Hamster Fibroblasts to Topoisomerase II Inhibitors¹

URA147 Centre National de la Recherche Scientifique, Physicochimie et Pharmacologie des Macromolécules Biologiques, Unité de Biochimie-Enzymologie, Institut Gustave Roussy, 94805 Villejuif cedex, France

In the Chinese hamster lung cell line DC-3F/9-OH-E, made resistant to 9-OH-ellipticine and cross-resistant to other topoisomerase II inhibitors, the amount of topoisomerase II is 4–5-fold lower than in the parental DC-3F cells. A mutation in position 1710 of topoisomerase IIß cDNA, generating a stop codon, completely abolishes the expression of this isoform in DC-3F/9-OH-E cells. To analyze the contribution of the loss of topoisomerase IIß to the resistance phenotype, DC-3F/9-OH-E cells were cotransfected with two plasmids, one conferring the resistance to G418, the other carrying the topoisomerase IIß cDNA. Among 200 G418-resistant clones, one was found to contain a topoisomerase IIß activity similar to that in the parental cells. These cells constitute an in vivo mammalian model to study the pharmacological role of topoisomerase IIß. In the transfected cells, different levels of cleavable complex formation and resistance reversion were observed with each topoisomerase II inhibitor examined. This work demonstrates that topoisomerase IIß is a pharmacological target for 9-OH-ellipticine, etoposide, or 4'-(9-acridinylamino) methanesulfon-m-anisidide and plays a role in the cytotoxicity of these agents. Furthermore, topoisomerase IIß is the preferential target for 4'-(9-acridinylamino)methanesulfon-m-anisidide. The loss of topoisomerase IIß activity in the DC-3F/9-OH-E cells is then in part responsible for their resistance to topoisomerase II inhibitors.

¹ Supported in part by Association pour la Recherche sur le Cancer, Villejuif, France, and by Ligue Nationale Française contre le Cancer, Paris, France.

² To whom requests for reprints should be addressed, at Unité de Biochimie-Enzymologie, Institut Gustave Roussy, P.R.II, 94805 Villejuif cedex, France.

Received 3/21/97. Accepted 8/ 1/97.

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